Abstract

The present study investigated the mechanism by which theophylline decreases cis-diamminedichloroplatinum(II) (DDP)-induced DNA crosslinking in L1210 cells. Alkaline elution of DNA from L1210 cells treated with DDP in the presence and absence of 1 mM theophylline showed that theophylline decreased interstrand crosslinking by 20%. DNA-protein crosslinking (PXL) immediately following platinum removal (used as a measure of active drug delivered to the cell nucleus) was not altered by theophylline nor were the kinetics of either DNA interstrand (ISC) or DNA-protein crosslink formation after DDP treatment changed by the presence of theophylline. Peak protein crosslinking occurred 6 hr and peak interstrand crosslinking occurred 12 hr after DDP removal. We measured crosslink removal by using thiourea to block the conversion of platinum monoadducts to crosslinks. DNA-protein crosslinks were removed more rapidly in the presence of theophylline. There was no change in interstrand crosslink removal rate when theophylline was present. We conclude that the addition of theophylline to DDP treatment results in decreased amounts of DNA interstrand crosslinking most likely by increasing the removal of DPP-DNA monoadducts. This latter process may be reflected by the increased removal rates for DNA-protein crosslinks.

title = "cis-Diamminedichloroplatinum(II) (DDP)-induced crosslinking and crosslink removal in L1210 cells in vitro after theophylline co-treatment",

abstract = "The present study investigated the mechanism by which theophylline decreases cis-diamminedichloroplatinum(II) (DDP)-induced DNA crosslinking in L1210 cells. Alkaline elution of DNA from L1210 cells treated with DDP in the presence and absence of 1 mM theophylline showed that theophylline decreased interstrand crosslinking by 20%. DNA-protein crosslinking (PXL) immediately following platinum removal (used as a measure of active drug delivered to the cell nucleus) was not altered by theophylline nor were the kinetics of either DNA interstrand (ISC) or DNA-protein crosslink formation after DDP treatment changed by the presence of theophylline. Peak protein crosslinking occurred 6 hr and peak interstrand crosslinking occurred 12 hr after DDP removal. We measured crosslink removal by using thiourea to block the conversion of platinum monoadducts to crosslinks. DNA-protein crosslinks were removed more rapidly in the presence of theophylline. There was no change in interstrand crosslink removal rate when theophylline was present. We conclude that the addition of theophylline to DDP treatment results in decreased amounts of DNA interstrand crosslinking most likely by increasing the removal of DPP-DNA monoadducts. This latter process may be reflected by the increased removal rates for DNA-protein crosslinks.",

N2 - The present study investigated the mechanism by which theophylline decreases cis-diamminedichloroplatinum(II) (DDP)-induced DNA crosslinking in L1210 cells. Alkaline elution of DNA from L1210 cells treated with DDP in the presence and absence of 1 mM theophylline showed that theophylline decreased interstrand crosslinking by 20%. DNA-protein crosslinking (PXL) immediately following platinum removal (used as a measure of active drug delivered to the cell nucleus) was not altered by theophylline nor were the kinetics of either DNA interstrand (ISC) or DNA-protein crosslink formation after DDP treatment changed by the presence of theophylline. Peak protein crosslinking occurred 6 hr and peak interstrand crosslinking occurred 12 hr after DDP removal. We measured crosslink removal by using thiourea to block the conversion of platinum monoadducts to crosslinks. DNA-protein crosslinks were removed more rapidly in the presence of theophylline. There was no change in interstrand crosslink removal rate when theophylline was present. We conclude that the addition of theophylline to DDP treatment results in decreased amounts of DNA interstrand crosslinking most likely by increasing the removal of DPP-DNA monoadducts. This latter process may be reflected by the increased removal rates for DNA-protein crosslinks.

AB - The present study investigated the mechanism by which theophylline decreases cis-diamminedichloroplatinum(II) (DDP)-induced DNA crosslinking in L1210 cells. Alkaline elution of DNA from L1210 cells treated with DDP in the presence and absence of 1 mM theophylline showed that theophylline decreased interstrand crosslinking by 20%. DNA-protein crosslinking (PXL) immediately following platinum removal (used as a measure of active drug delivered to the cell nucleus) was not altered by theophylline nor were the kinetics of either DNA interstrand (ISC) or DNA-protein crosslink formation after DDP treatment changed by the presence of theophylline. Peak protein crosslinking occurred 6 hr and peak interstrand crosslinking occurred 12 hr after DDP removal. We measured crosslink removal by using thiourea to block the conversion of platinum monoadducts to crosslinks. DNA-protein crosslinks were removed more rapidly in the presence of theophylline. There was no change in interstrand crosslink removal rate when theophylline was present. We conclude that the addition of theophylline to DDP treatment results in decreased amounts of DNA interstrand crosslinking most likely by increasing the removal of DPP-DNA monoadducts. This latter process may be reflected by the increased removal rates for DNA-protein crosslinks.